The invention relates to a process of preparing a compound of the formula ##STR2##
wherein R.sup.1 is aryl, heteroaryl, substituted aryl or substituted heteroaryl and R.sup.2 is hydrogen, alkyl or aralkyl, or salt thereof.
Compounds of Formula I are useful as intermediates in the synthesis of, inter alia, compounds described in WO 97/41102. Compounds described in WO 97/41102 are antagonists of the platelet fibrinogen receptor (gp IIb/IIIa antagonist) and thus are useful for treating platelet-mediated thrombotic disorders such as arterial and venous thrombosis, acute myocardial infarction, reocclusion following thrombolytic therapy and angioplasty, inflammation, unstable angina and vaso-occlusive disorders.
Known methods for preparing compounds of Formula I include an asymmetric Michael addition of lithium (R)-N-(trimethylsilyl)-(1)-phenethylamide to ethyl 3-pyridyl acrylate to give the ethyl .beta.-aminoester disclosed in U.S. Pat. No. 5,254,573. This process results in inefficient formation of lithium amide and difficult removal of N-(-methylbenzyl) group.
J. Org. Chem. vol. 61, p. 2222 (1996) discloses a process wherein the lithium enolate of ethyl acetate is added to an enantiomoric sulfinimine, the product of which is purified by chromatography and deprotected under acidic conditions to afford the .beta.-amino ester in greater than 90% ee. The need for chromatographic purification makes this process unattractive for large-scale production.
WO 98/02410 discloses a process of stereoselective addition of the Reformatsky reagent prepared from t-butylbromoacetate to the enantiomeric imine prepared from 3-pyridine carboxaldehyde and (R)-2-phenylglycinol. Oxidative cleavage of the N-(1-phenyl-2-hydroxy ethyl) group with NaIO.sub.4 in ethanol followed by acid hydrolysis affords the enantiomerically pure t-butyl .beta.-amino ester. Use of oxidizing agents makes this process unattractive for large-scale production.
WO 97/41102 discloses enzymatic resolution of the (.+-.).beta.-phenylacetamido acid using penicillin amidase to afford the S-acid. This process, which utilizes enzymes, is inefficient and impractical for large scale production.
Thus there exists a need for a process which is compatible with large scale production needs and which achieves acceptable levels of purity and yield.